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SummaryApproximately 14% of transfused hemophiliacs develop an anti-factor VIII inhibitory antibody which specifically neutralizes factor VIII procoagulant activity. In this study an association of the major histocompatibility complex (MHC) with inhibitor antibody formation was evaluated by restriction fragment length polymorphism (RFLP) analysis using BamHI, EcoRI, HindII, PstI, PvuII and TaqI digested genomic DNA probed with DP beta, DQ alpha, DQ beta and DR beta class II MHC gene probes. The RFLP patterns for 16 non-inhibitor and 11 inhibitor hemophiliac patients were analyzed. These 24 enzyme:probe combinations generated 231 fragments. Fifteen (15) fragments associated with the inhibitor phenotype; odds ratios ranged from 5.1 to 45 and lower bounds of 95% confidence intervals were > 1.000 for all 15 fragments. Five (5) fragments associated with non-inhibitors, with odds ratios ranging from 6.4 to 51.7. This report establishes a MHC related genetic basis for the inhibitor phenotype. No statistically significant differences in the distribution of serologically defined HLA-DR phenotypes were observed between the inhibitor and non-inhibitor groups.

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High fat diets were given ad libitum or force-fed to rats. The incidence of thrombosis in animals fed a cow butter diet was higher than in those fed a cocoa butter diet. No thrombosis was found in rats fed a diet containing peanut oil. Coagulation studies performed at weekly intervals on blood samples obtained from a tail vein of rats fed the diets ad libitum showed that there was a gradual but marked increase in the levels of Factors II, VII, and X of animals fed a diet containing cow or cocoa butter, but not one containing peanut oil. Several weeks prior to death, however, the level of all coagulation factors, including Factors I and V, fell. A significant prolongation of the values for the partial thromboplastin time was found in animals killed at the time when levels of plasma coagulation factors decreased. The pattern of changes in concentration of plasma coagulation factors was similar in the groups of animals dying with proven thrombosis and in those in which thrombosis was not found. All rats force-fed the above two diets died within two weeks, showing a marked fall in all coagulation factors and no thrombosis. Weight loss was more pronounced in the groups of animals fed the diet containing cow butter and cocoa butter than in animals fed Purina chow. Autopsy findings were: intra-ventricular thrombi with myocardial infarction, lung hemorrhage, pneumonia, and rarely jaundice. No cause of death other than inanition was discernible in some of the animals. Marked fatty infiltration of the liver was a feature of all animals autopsied.

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The prothrombin time was followed in a large number of rats receiving daily doses of dicumarol. Prothrombin times, using the Schwager–Jaques method, were determined on blood samples obtained from the tail vein. It was found that rats, like rabbits, showed a wide variation in their response to dicumarol at dose levels of 10 and 20 mg./kg. body weight per day but, unlike rabbits, they seemed to develop a tolerance to the drug. This began after a peak prothrombin time was reached and occurred later in rats having a higher prothrombin time, or receiving the higher dose of the drug. Stress, in the form of electroshock or sound-induced seizures, increased the variability of the prothrombin time and significantly increased the mean values with 20 mg./kg. dicumarol. These changes persisted in some rats for at least 48 hours. They were prevented by ether anesthesia. Adrenalectomized rats fed dicumarol showed a marked increase in prothrombin time, did not develop tolerance to the drug after a few days, and died of hemorrhage. An analysis of blood samples obtained by cardiac puncture from adrenalectomized, sham-operated, and normal rats fed dicumarol at a dose level of 10 mg./kg. body weight for 5 days showed that values for the Quick one-stage prothrombin times of the adrenalectomized group were elevated significantly above those of the sham-operated and normal groups. No significant differences, however, were noted in the values for the two-stage tests for prothrombin, hematocrit, or plasma dicumarol levels of these animals.

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